Derivative {[2- (amino-3,4 - dioxo-1 - cyclobutene-1-yl) amino] alilovic}acids

 

(57) Abstract:

Usage: in medicine, in particular as protivogololednyh and narsasidadir substances in cases involving excessive release of excitatory amino acids. The inventive product f-ly I, where R1hydrogen, C1-C6alkyl or phenylalkyl with C7-C12R2is hydrogen, C1-C6alkyl, C2-C6alkenyl or phenylalkyl with C7-C12or R1and R2together the group: CH2-CH2-(CH2)-CR6R7-CH2or -(CH2)-CR8R9-CR10R11-CH2in which R6R8R10independent from each other hydrogen, C1-C6alkyl or hydroxyl, R7, R9, R11independent from each other hydrogen or C1-C6alkyl; And - C1-C6-alkylene or C2-C6-albaniles; X the group-C(O)OR3when R3hydrogen, C1-C6-alkyl or P(O)(OR4)(OR5) when R4, R5independent from each other hydrogen, C1-C6-alkyl, 3,5-dioxo-1,2,4-oxadiazolidine-2-yl or 5-tetrazolyl, or their pharmaceutically acceptable salts. Reagent 1: connection f-crystals II, where R1see above, R12-Alcock is NR2-A-X where R2A and X see above. Reaction conditions: in the midst of the solvent at room temperature or when heated. The connection structure of f-crystals I and II: I II. table 1.

Excitatory amino acids such as glutamic acid was found to be important neurotransmitters (Johnson, R. L. Kerner, J. F. J. Med.Chem. 1988, T. 31, page 2057), which in excess participate in the sequence of events leading to neural damage after cerebral ischemia (Choi, D. U. Trends Neurosci, 1988, T. II, page 465). One of the major subtypes of receptor excitatory amino acids is the NMDA-receptor, which is determined by the agonist, N-methyl-D-aspartic acid (NMDA). Blocking the actions of endogenous agonist selected an antagonist of the NMDA-receptor, 4-(3-photoprobes)-2-piperazinecarboxamide acid (RAF) has been found to prevent ischemic disorders in the brain of gerbils (Boast, K. A. and other Brain Research 1988, I. 442, page 345). In addition, the NMDA-induced seizures can be prevented with the help of the RAF in mice (Lehmann, J. and other J. Pharmacol Exp. Ther. 1987, I. 240, page 737). Finally, competing the NMDA-antagonists such as the RAF was found to prevent symptoms resembling zabolevaniy 1991, so 349, page 414). For these reasons, the NMDA-receptor antagonists are considered as suitable materials for the treatment of epilepsy, stroke (Engelsen, B. Acta Neurol Scand 1986, T. 74, page 337) and neurodegenerative disturbances such as disease Alzheimer (Maragos, U. F. and other Trend Neurosci 1987, T. 10, page 65) and Parkinson's disease.

Chemical materials, known as competitive antagonists of NMDA receptors, contain functionality-amino-carboxylic acids and alkylphosphines acid, which are separated by a set of blocks ("spacers"). "Nereocystis" example is 2-amino-5-bostonballerina acid (AR) [1] (Watkins, J. To. Evans, R. H. Annu. Rev. Pharmacol. Toxicol 1981, T. 21, page 165), which contains a saturated carbon chain. More complex examples that contain elements that increase the structural rigidity and, consequently, the power of impact include the RAF (see above), CIS-4-(phosphonomethyl)-2-piperidinylcarbonyl acid (GS-19755) (Lehmann, J. and other J. Pharmacol Exp. Ther. 1988, T. 246, page 65) [2] and (E)-2-amino-4-methyl-5-foston-3-pontenova acid (GP-37849) (Schmutz, M. and other Abs. Soc. Neurosci. 1988, so-14, page 864) [3] Although efforts were made to find groups that are bioisosterism with a group alkylphosphonic acid (Canard, which would confirm bioisosterism substitution functionality-aminocarbonyl acid.

In accordance with the invention offers the group N-substituted derivatives of 3,4-diamino-3-cyclobutene-1,2-dione, which are the NMDA-antagonists which are "recognized" by the relevant receptors and which prevents NMDA-induced lethality in vivo. Effective when used as protivogololednyh agents and narsasidadir agents in cases involving excessive release of excitatory amino acids, compounds that are the subject of the invention represented by structural formula I

where R1is hydrogen, alkyl with 1-6 carbon atoms, or phenylalkyl with 7-12 carbon atoms;

R2is hydrogen, alkyl with 1-6 carbon atoms, alkenyl with 2-6 carbon atoms or phenylalkyl with 7-12 carbon atoms; or

R1and R2taken together, form Z, which are-CH2CH2-, -CH2WITH(R6)(R7)CH2- or-CH2C(R8)(R9)-C(R10)(R11)CH2-, where R6, R8and

R10are independently from each other hydrogen, alkyl with 1-6 carbon atoms, or hydroxyl, and R7, R9and R11are independently from each other hydrogen or alkyl containing the kind;

X is the CO2R3in which R3is hydrogen or alkyl with 1-6 carbon atoms, P(O)(OR4OR5), in which R4and R5are independently from each other hydrogen or alkyl with 1-6 carbon atoms, 3,5-dioxo-1,2,4-oxadiazolidine-2-yl or 5-tetrazolyl; or acceptable from a pharmaceutical point of view of salt.

Examples of alkyl for R1-R5and R6-R16see above, are linear or branched group such as methyl, ethyl, n-propyl, isopropyl, butyl and hexyl. Preferred alkyl groups contain from 1 to 4 carbons. Examples of alkenyl for R2are linear or branched group such as vinyl, prop-1-enyl, alkyl, methallyl, but-1-enyl, but-2-enyl and but-3-enyl.

Examples phenylalkyl groups for R1and R2are such groups in which the alkyl part is linear or branched chain such as benzyl, phenetyl, 3-phenyl-propyl, 4-phenyl-butyl. In a preferred embodiment, the alkyl component of the group contains 1-4 carbon atoms.

Preferred values for R1 and R2are, independently of one another, hydrogen, methyl, allyl, methallyl and benzyl, and when the/SUB>- or-CH2WITH(R8)(R9)-C(R10)(R11)CH2-, where R6, R8and R10independently are hydrogen, alkyl with 1-6 carbon atoms or hydroxyl, and R7, R9and R11independently of one another are hydrogen or alkyl with 1 to 6 atoms and carbon atoms. Examples alkilinity groups And are linear or branched group, in the preferred embodiment, the groups containing from 1 to 4 carbon atoms, such as-CH2-, -CH2CH2-, -CH(CH3)-CH2, -CH2CH(CH3)-, -(CH2)3- and -(CH2)4-. Examples alkenilovyh groups are CIS and TRANS groups in the preferred embodiment, containing 2-4 carbon atoms such as-CH2-CH= CH-, -CH= C(CH3)-, -C(CH3)= CH, -CH=CH-CH2- and-CH2--CH=CH-CH2- and-CH2-CH= C(CH3)-. In the preferred embodiment, And is alkylene with 1-4 carbon atoms or TRANS-2-butylene. The preferred values for X is carboxyl, phosphonyl or 5-tetrazolyl.

Acceptable from a pharmaceutical point of view salts of the compounds of the subject invention include the salts of alkali metals (sodium, potassium or lithium), alkaline earth m the I method of preparing compounds of formula I.

Therefore, in accordance with the invention proposes a method of obtaining compounds of formula I, which includes:

a) interaction of the compounds of formula II

where R1defined above; OR12is any alkoxy or Alcoxy-substituted group such as those that have 1-6 and 7-12 carbon atoms, respectively, for example, methoxy, ethoxy, benzyloxy, with the compound of the formula III

HNR2-A-X, in which R2And X have been defined above, or its salt, or a protected form if necessary to remove any protecting group to obtain the compound of formula I, where R2was defined above, if necessary, be isolated in a form acceptable from a pharmaceutical point of view, or

b) interaction of the compounds of formula IV

where X, R2and R12defined above, or its salt or protected form with the compound of the formula V

H2NR1where R1was defined above, and removing any protecting groups to obtain the corresponding compound of formula I or its salt; or

(C) the interaction of the compounds of formula VI

where R12has already been defined above, which may be identical or different, with the compound of the formula VII

H2N-Z-NH-A-X, Genie any protecting group, to obtain the corresponding compound having the formula (I) in which R1and R2taken together, represent the Z and X were defined above; or

d) removing the protection, selective, if necessary, and cyclization of the compounds of formula VIII

where X, Z, R12and As has already been defined above, or X may be-SP, or its salts, its protected form, and R is an amino-protecting group, which in the preferred embodiment, is selectively removed, if X is protected, to obtain a corresponding compound having the formula (I), where R1and R2are Z, if, in addition, required removing any protecting group on X; or

(e) the interaction of the compounds of formula IX

where R1, R2and As has already been defined above, with an azide such as alkali metal azide, for example, NaN3or azide inputs of TBT to obtain the corresponding compound of formula I in which X is 5-tetrazolyl; or

f) the conversion of compounds of formula (I) in which R3, R4and R5are alkyl groups, in order to obtain the compounds of formula (I) in which R3, R4and R5are hydrogen, or their salts; or

g) the acidification of the salts of the compounds of formula I to get free the crystals X

where R1defined above; X1is the CO2R3or-RO(OR4)(OR5), where R3, R4and R5all are alkyl, 3,5-dioxo-1,2,4-oxadiazolidine-2-yl or protected 5-tetrazolyl, Oh1- represents alkylene with 2-6 carbon atoms, substituted-S(O)m-aryl radical, where m is 1 or 2, if required removing any protecting groups to obtain the corresponding compound of formula (I) in which a is Alcanena with 2-6 carbon atoms. Examples of aryl are monovalent aromatic hydrocarbons containing from 7 to 12 carbon atoms, for example, phenol, tolyl, etc.

In some of these reactions, when it is desirable to obtain X in the form of carboxy or alkylphosphines acid, it may be necessary or important to protect such groups during the reaction or to use its derivative WITH1-C6Olkiluoto of ester, for example, tert-butyl ether complex, and then to remove them. Examples of carboxy protecting groups are benzyl esters or esters with 7 or more carbon atoms.

Similarly, when X is 5-tetrazolyl, this group can be protected using the standard pickup is in securitization. In addition, when R6, R8and R10are hydroxy, the corresponding protected during the reaction can be carried out octiles, bentilee, tert-butilkoi, trailvoy, and in the preferred embodiment, benzyl group.

With regard to method (a), the displacement alkoxy or Alcoxy-substituent of the compounds of formula II may be suitably carried out in the absence of a base or with a base such as a hydroxide of alkaline metal (e.g., NaOH) during heating or in the presence of an inert solvent such as ethanol. When X is an acid component in the compound of formula III under alkaline reaction conditions, the product is salt, which can be isolated as such or converted to the free acid by acidification. When X is a carboxylic acid function, it can be protected, for example, in the form of ester or salt with a cation.

As for method b), the substitution OR12groups can be carried out using ammonia or an amine of the formula H2NR2in the presence of an inert solvent such as ethanol with heating or without him, the group X protect, if necessary.

Method (e) can be carried out using alkali metal azide in an inert solvent such as dimethylformamide in the presence of ammonium chloride when heated, if necessary. If using azide presence of TBT, the reaction can be performed in an inert solvent such as toluene, and then perform acidification.

With regard to process (f), when any one of R3or R4and R5is an alkyl group, they may be removed by hydrolysis and other known methods, to obtain the corresponding free acids or their salts.

Thermolysis of compounds of formula X can be carried out by heating an inert solvent with high boiling point such as toluene in presets the same way, this method can be used to get the raw materials used in the described method, where it is desirable to obtain compounds in which a represents albaniles.

In accordance with the invention are also intermediate compounds for preparing compounds of formula (I). To these intermediate compounds are compounds having formula IV, VIII, which are listed and defined above, and, in addition, intermediate compounds for compounds of formula IV, which are intermediate compounds having the formula XI

< / BR>
These intermediate compounds can be represented by one of General formula XII

or their salts,

where X2is JV, R14where R14is hydrogen, alkyl with 1-6 carbon atoms or a carboxyl protecting group, -RO(OR15)(OR16), in which R15and R16are hydrogen or alkyl with 1-6 carbon atoms, 3,5-dioxo-1,2,4-oxadiazolidine or perhaps protected 5-tetrazolyl, R12and As has already been defined above, and R13represents hydrogen, alkyl with 1-6 carbon atoms, alkenyl with 2-6 carbon atoms, phenylalkyl with 7-12 carbon atoms, or-Z-NHP, where P is an amino-about obtain the intermediate compounds of formula VI, defined above, with a compound of formula XIII

HR13N-A-X2where A, R13and X2defined above, to obtain the corresponding compound of formula XII, or

N-alkylation of compounds of formula

in which R12And X2have already been defined above, in the presence of a strong base, for example NaH, with the compound of the formula R2-halogen, where halogen is a halogen such as chlorine or bromine, and R2defined above, except hydrogen to obtain the corresponding compound of formula XII.

The source materials used in any of the mentioned methods to obtain the final products and intermediates are compounds or they can be obtained using methods analogous to known compounds.

Compounds of the invention are produced by known methods, including (I) the substitution of the alkoxy substituent of 3-amino-4-alkoxy-3-cyclobutene-1,2-dione amino acid (H2NAX) in the presence of an equivalent mass of hydrate of sodium oxide to obtain derivatives in which R2is hydrogen;

(2) the interaction of 3,4-dialkoxy-3-cyclobutene-1,2-dione with an amine (N2NR2with subsequent N-Alky is lsua sodium hydride as the base, followed by filling the remaining alkoxy-substituent with the required amine (N2NR1and removing the protecting tert-butyl ether complex acid such as formic acid and (3) similarly, 3,4-dialkoxy-3-cyclobutene-1,2-dione can interact with the corresponding amino acid (H2N-A-PO3Et2to replace one alkoxy group, and this intermediate compound can be N-alkylated in dimethylformamide with the corresponding alkylhalides (R2is halo) in the presence of sodium hydride and/or other alkoxy-Deputy may be replaced with the appropriate amine (N2NR1). The resulting ester phosphonate converted into the free acid by means of bromotrimethylsilane. Using a diamine such as H2N-(CH2)n-NHCH2CH2PO3Et2(n= 2-4), 3,4-diethoxy-3-cyclobutene-1,2-dione get esters dioxoazabicyclooctadiene acid such that illustrated in example 7, below. Ester phosphonate converted into the free acid by known technique. Source diamino reagents receive as a result of the interaction of N-protected alkylenediamines complex with diethyl ether (2-oxoethyl/alkylphosphonic acid in the presence of cyanoborohydride sodium in methanol LASS="ptx2">

In addition, (4) the original mono-protected diaminopentane reagents are produced by interaction of N-protected alkylenediamines with Br-A--PO3Et2in the presence of sodium carbonate in ethanol. Monogamistic dimentsional such as protecting group (-NH-(CH2)n-NH-A-PO3Et2(n=2-4) interacts with 3,4-dialkoxy-3-cyclobutene-1,2-dione to displace one alkoxygroup. Remove benzyloxycarbonyl N-protecting group by hydrogenation or tert-butyloxycarbonyl N-protecting group by treatment with formic acid leads to cyclization. The resulting esters dioxoazabicyclooctadiene acid is subjected to hydrolysis to the free acid by means of bromotrimethylsilane;

(5) mono N-benzyloxycarbonyl diamine may be alkylated using a Br-A-CO2-tert-Bu in the presence of diisopropylethylamine in dimethylformamide. The intermediate connection Z-NH-(CH2)n-NH-A-CO2-tert-Bu, interacts with 3,4-dialkoxy-3-cyclobutene-1,2-dione to displace alkoxy group. Removing the N-protecting group by hydrogenation of the intermediate leads to cyclization. Tert-butyl group split when PI alkylated with VG-AND-SP using a known technique. Intermediate compound BOC-NH-(CH2)n-NH-A-CN interacts with 3,4-dialkoxy-3-cyclobutene-1,2-dione to displace one alkoxygroup. Removing the N-protecting group by treatment with formic acid leads to cyclization. The nitrile is converted into tetrazole by heating with sodium azide and ammonium chloride in dimethylformamide. If Allenby bridge diamine contains hydroxyl group, it is possible to protect on this reaction.

In all of these reactions the reactants are either known or available in the market, or you can get them easily if itooshi techniques, known to every expert in the field of medicinal chemistry.

Compounds of the invention can contain one or more asymmetric carbon atoms (for example, when any one of R6-R10is alkyl or any of R6, R8and R10is hydroxyl), so the proposed compounds can exist in different stereoisomeric forms. All stereoisomeric forms included in the scope of the claims of the invention. Such compounds can be, for example, racemates, optically active forms. Optically active forms can be obtained by dividing the rat is a-alanine.

A solution of 3-amino-4-ethoxy-3-cyclobutene-1,2-dione (2.0 g, 14 mmol) in ethanol (100 ml) was treated-alanine (1.26 g, 14 mmol) dissolved in 1 N. the solution of hydrate of sodium oxide (14 ml, 14 mmol). After 5.5 hours at room temperature, the resulting yellow solid material was filtered, washed with ethanol and concentrated under high vacuum to obtain the pure compound of the title of example in the form of sodium salt, hemihydrate (2.6 g, 86% of theoretical, melting point 280-282aboutC);

IR (KBR, cm-1): 1810; MS (-FAB) 205 (M-H, 13), 183 (M-Na, 44), 175 (17), 148 (100); 1H-NMR (D2O, 400 MHz): 3,59 (broad singlet, 2H), 2,31 (triplet, J=6 Hz, 2H);

13C-NMR (D2Oh, 400 MHz): ppm 182,01, 181,61, 179,30, 168,94, 168,54, 41,18, 37,97.

Calculated With 39,08; N. Of 3.75; N 13,02.

WITH7H7NaN2O41/2 H2O

Found, C 38,78; N 3,48; N 12,86.

a) using the same procedure, condensing the stoichiometric quantity of 3-amino-4-ethoxy-3-cyclobutene-1,2-dione with acylglycerol receive the ethyl ester of N-(2-amino-3,4-dioxo-1-cyclobutenyl)glycocol, the melting point 231-233aboutC.

Calculated With 48,49; N 5,09; N 14,14.

WITH8H10N2O4< / BR>
Found, butenyl)glycocol in the form of salts of sodium, 4/3 H2Oh, the melting point of 210-215aboutWith (Razlog.).

Calculated With 33,34; N To 3.58; N 12,96.

WITH6H5NaN2O44/3 H2ABOUT

Found, 33,36; N 3,26; N 13,12.

(C) Similarly, replacing 4-aminobutanoic acid-alanine in the procedure of example 1 gives 4-[(2-amino-3,4-dioxo-1-cyclobutenyl/amino]butane acid salts of sodium, partial hydrate, melting point 240-243aboutWith (Razlog.).

Calculated With 41,67; N. Of 4.44; N 12,15.

WITH8H9NaN2O40.58 N2ABOUT

Found, 41,27; N. Of 4.04; N A 12.03.

P R I m e R 2. 2-[2-[(2-Amino-3,4-dioxo-1-cyclobutene-1-yl)amino]ethyl] 1,2,4-oxadi - solidin-3,5-dione.

A solution of 3-amino-4-ethoxy-3-cyclobutene-1,2-dione (0.56 g, 4.0 mmole) in ethanol (20 ml) was added to bromohydrin 2-(2-amino-ethyl)-1,2,4-oxadiazolidine-3,5-dione (from 0.90 g, 4.0 mmol) in ethanol (100 ml). The reaction mixture was treated with 1 N. a solution of hydrate of sodium oxide (8 ml, 8 mmol) and was stirred for 24 h at room temperature. The precipitate was filtered, dissolved in water and passed through an ion-exchange column (AG 50W-x2, 100-200 mesh (0,149-0,074 mm), N+-form), elwira water. Eluent was freeze dried, resulting in poluchaeetsa the melting point 225aboutWith (Razlog.),

IR (KBR, cm-1) 3300, 3140, 1820, 1740, 1720, 1640; MS (+FAB) 241 (MN+);1H NMR (DMSO, 400 MHz): 12,4 (broad singlet, NH), and 7.5 (broad singlet, 3NH), of 4.0-3.5 (multiplet, 4H);13C-NMR (DMSO, 400 MHz): ppm 183,72, 183,63, 170,06, 168,96, 158,17, 152,72, 50,41, 41,68.

Calculated C 38,70; N 3,61 N 22,56.

WITH8H8N4ABOUT50,45 N2ABOUT

Found, 39,10; N 3,24; N 22,19.

a) The same reaction conditions as described in examples 1 and 2, applied to alanine and 4-ethoxy-3-methylamino-3-cyclobutene-1,2-dione, gave N-[2-(methylamino)-3,4-dioxo-1-cyclobutenyl] beta-alanine in the form of sodium salt, 1/4 H2Oh, melting point 310aboutWith (Razlog.).

Calculated With 42,77; N 4.26 Deaths; N 12,47.

WITH8H9NaN2O41/4H2ABOUT

Found, 42,77; N 3,88; N 12,53.

b) Similarly, 3-benzylamino-4-ethoxy-3-cyclobutene-1,2-Dion, when he interacted with-alanine, 3 gives[[3,4-dioxo - 2[(phenylmethyl)amino]-1-cyclobutenyl] amino] propanoic acid sodium salt, 1/2 H2Oh, the melting point 298-302aboutWith (Razlog.).

Calculated With 55,08; N To 4.62; N 9,18.

WITH14H13NaN2O41/2 H2ABOUT

Found, C 54,74; N A 4.53; N 9,06.

P R I m e R 3. N(5,2 g, 31 mmol) in ethanol (80 ml) was treated at room temperature with allylamine (2.3 ml, 31 mmol) which was dissolved in ethanol (40 ml) for 2 h the Reaction mixture was concentrated under vacuum to obtain crude 1-(2-propylamino)-2-ethoxy-3,4-dioxo-1-CEC - Labuan as a pale yellow solid (5.6 g). The crude intermediate compound was dissolved in anhydrous dimethylformamide (50 ml) and was added dropwise to a suspension of 60% sodium hydride (1.5 g, 37 mmol) in anhydrous dimethylformamide (50 ml) under nitrogen atmosphere. Anion rapidly cooled tert-butyl bromoacetate (6,0 ml, 37 mmol) and the reaction mixture was stirred 1.5 h, poured into water (500 ml), extracted with ethyl acetate (CH ml) and dried (magnesium sulfate) to obtain 1.1-dimethylethylamine ester of N-(2-ethoxy-3,4-dioxo-1-cyclobutene-1-yl)-N-(2-propenyl)- glycocol. Purification was carried out using the operational chromatography (10 cm diameter, elution with 20% ethyl acetate in petroleum ether) and then received a yellow oil (4,56 g, 50%);

1H-NMR (CDCl3, 300 MHz): 5,88-5,72 (multiplet, 1H), 5,35-5,22 (multiplet, 2H), 4.80 to 4,68 (multiplet, 2H), 4,35, 4,08 (doublet, J=7 Hz, 2H), 4,28, 3,95 (singlet, 2H), 1,48 (singlet, N), 1,45 (triplet, J=7 Hz, 3H).

An ethanol solution of ammonia (25 ml) was added to the flasks is 8.5 mmol), at room temperature. After 5 h the reaction mixture was concentrated and subjected to purification using operational chromatography (5 cm diameter, elution with 5% methanol in dichloromethane) to obtain 1,1-dimethyl-ethyl ester N-(2-amino-3,4-dioxo-1-cyclobutene-1-yl)-N-(2-propenyl)glycocol in the form of a white solid (1.6 g, 71% melting point 175-176aboutC).

IR (KBR, cm-1): 3300, 3140, 1810, 1740, 1670, 1650; MS (E1): 266 (M+, 34), 210 (24), 165 (100), 109 (54), 95 (89), 68 (68);1H-NMR (DMSO, 400 MHz): 6,70 (broad singlet, NH2), of 5.84-5,77 (multiplet, 1H), 5,26 (doublet, J=17 Hz, 1H), 5,19 (doublet, J=10 Hz, 1H), 4,3-4,0 (broad multiplet, 4H), 1.39 in (singlet, N).

To unprotect a 1,1-dimethyl ethyl ether complex of N-(2-amino-3,4-dioxo-1-cyclobutene-1-yl)-N-(2-propenyl)glycol (1.6 g, 6.0 mmol) was carried out by mixing in formic acid (20 ml) for 24 h the Reaction mixture was concentrated, subjected azeotrope dichloromethane and accompanied by difficulties recrystallization (several times removed oil), to obtain a connection from the header of example, 1/4 hydrate, in the form of not-quite-white solid (0,80 g, 62% of the melting point 172-175aboutC).

IR (KBR, cm-1): 3330, Le, HE, of 7.70 (singlet, NH2), 5,86-5,77 (multiplet, 1H), 5,26 (doublet, J=17 Hz, 1H), 5,19 (doublet, J=10 Hz, 1H), 4,3-4,0 (broad multiplet, 4H).

Calculated, 50,35; N Is 4.93; N Of 13.05.

WITH9H10N2O41/4 H2ABOUT

Found, 50,13; N 4,82; N 12,86.

a) Following the procedure of example 3, except that 2-methylethylamine used as a starting reagent was obtained N-(2-amino-3,4-dioxo-1-cyclobutenyl)-N-(2-methyl-2-propenyl)glycocol, the melting point 184-186aboutC.

Calculated With 53,14; N 5,44; N KZT 12.39.

C10H12N2ABOUT40.1 G2ABOUT

Found, C 53,09; N 5,38; N 12,16.

b) Similarly, using benzylamine as a source of reagent, according to the procedure of example 3 was obtained N-(2-amino-3,4-dioxo-1-cyclobutenyl)-N-(Fe - ylmethyl)glycocol, the melting point 177-179aboutC.

Calculated From 60,00; N 4,65; N 10,76.

WITH13H12N2O4< / BR>
Found, 59,74; N 4,60; N 10,61.

P R I m e R 4. [2-[(2-amino-3,4-dioxo-1-cyclobutene-1-yl)amino]ethyl] phosphinic acid.

To a solution of 3,4-diethoxy-3-cyclobutene-1,2-dione (4,00 g, 23.5 mmol) in ethanol (100 ml) was added diethyl ester 2-aminoethylphosphonic Kolotilina was adsorbing on silica gel and subjected to purification using operational chromatography (5.5 cm diameter, gradient elution using a 2.5-10% isopropanol in dichloromethane) to obtain the diethyl ester of [2-[(2-ethoxy-3,4-dioxo-1-cyclobutene-1-yl)amino] ethyl] phosphinic acid in the form of oil, which solidifies after conditioning (3.98 g, 55% of the melting point 66-68aboutC).

IR (KBR, cm-1): 3400, 3180, 1800, 1700, 1600; MS (+FAB): 306 (MN+, 100), 278 (14), 137 (14), 109 (35).

1H-NMR (Dl3, 400 MHz): 6,58, 6,46 (broad singlet, NH), and 4.75 (broad multiplet, 2H), 4,21-4,07 (multiplet, 4H), 4.00 points, to 3.75 (broad multiplet, 2H), 2,08 (doublet of triplets, J=17.5 and a 6.5 Hz, 2H), 1,46 (broad multiplet, 3H), 1.35 (triplet, J=7 Hz, 6N).

A solution of ester diethyl [2-[(2-ethoxy-3,4-dioxo-1-cyclobutene-1-yl)amino] ethyl] phosphinic acid (1,69 g, 5.5 mmol) in 100% ethanol (100 ml) were placed in a flask equipped with a funnel and an inlet for nitrogen. Full ethano - levy ammonia solution (190 ml) was placed in an addition funnel and added over 1 h the Reaction mixture was stirred at room temperature during 24 h, and then concentrated under vacuum. The resulting solid was subjected to recrystallization from methanol in ethyl acetate to obtain the diethyl ester of [2-[(2-amino-3,4-dioxo-1-zienia 150-152aboutWith (Razlog.)).

IR (KBR, cm-1): 1805, 1650; MS (+FAB): 277 (MH+, 100), 182 (20), 109 (15).

1H-NMR (DMSO, 400 MHz): 7,5 (broad singlet, NH 3), a 4.1-3.9 (multiplet, 4H), 3,7-3,6 (multiplet, 2H), 2,11 (doublet of triplets, J=17.5 and 7.5 Hz, 2H), 1,22 (triplet, 6N).

Calculated With 42,92; N 6,27; N 10,01.

C10H17N2O5P 1/5 H2O

Found, With 42,90; N Equal To 6.05; N 10,00.

A suspension of diethyl ether complex [2-[(2-amino-3,4-dioxo-1-cyclobutene-1-yl)amino] ethyl] phosphinic acid, one-fifth hydrate (0,90 g, 3.2 mmol) in dry 1,2-dichloroethane (47 ml) were placed in a flask equipped with a reflux condenser and which had previously been pumped out the air and filled with nitrogen. Into the flask through a syringe was added bromotrimethylsilane (2,6 ml, 19.8 mmol) and the reaction mixture was delegirovali 10 minutes the mixture is Then concentrated under vacuum to get solid colors of rust, which was dissolved in deionized water (80 ml). The water washed diethyl simple ether (CH ml) and concentrated under vacuum. The resulting solid color rust was subjected to recrystallization from methanol and water in ethyl acetate, to obtain a connection from header example in the form of a dark yellow solid (1H-NMR (DMSO, 400 MHz): 7,5 (broad singlet, NH 3), to 3.67 (broad singlet, 2H), 1,85 (doublet of triplets, J=7.5 Hz, 2H).

Calculated With 32,21; N 4,24; N To 12.52.

WITH6H9N2O5P 1/5 H2O

Found, 32,20; 4,00; N 12,46.

a) Following the procedure of example 4, except that the diethyl ester aminomethylphosphonic acid was used as a reagent was obtained [[(2-amino-3,4-dioxo-1-cyclobutenyl)AMI - but]methyl]phosphinic acid in the form of three quarters hydrate, melting point 220-250aboutWith (Razlog.).

Calculated, 27,35; N 3,90; N 12,76.

WITH5H7N2O5R 3/4 H2ABOUT

Found, With 27,72; N 3,39; N KZT 12.39.

b) Again using diethyl ester 3-aminopropylphosphonic acid as reagent in the procedure of example 4 was obtained [3-[(2-amino-3,4-dioxo-1-cyclobutene-1-yl)amino]propyl]foshi - new acid, melting point 220-230aboutWith (Razlog.).

Calculated With 36,91; N 4,74; N 11,96.

WITH7H11N2O5P

Found, 35,94; N. Of 4.57; N 11,76.

C) complex With diethyl ether 4-aminobutyraldehyde acid as reagent in the procedure of example 4 was obtained [4-[(2-amino-3,4-dioxo-0-242aboutWith (Razlog.).

Calculated With 38,03; N 5,38; N 11,09.

WITH8H13N2O5P 1/4 H2ABOUT

Found, 38, 09; N 5,01; N 11,09.

P R I m e R 5. [(E)-4-[(2-amino-3,4-dioxo-1-cyclobutene-1-yl)amino]-2-butenyl] phosphinic acid.

A solution of diethyl ether complex [(E)-4-(N-phthalimido)-2-butene-1-yl] alkylphosphines acid (8,58 g, 25.4 mmol) in the shell of the nitrogen was obtained by the method Connel and other J. Org.Chem. so 54, page 3359 (1989) in ethanol (75 ml), then was treated with 85% hydrazine hydrate (5 ml) and brought to reflux distilled for 15 minutes Actually solid, the reaction mixture was concentrated and divided between 2.5 N. the solution of hydrate of sodium oxide (250 ml) and dichloromethane (150 ml) under stirring within 30 minutes After separation, the aqueous layer was again extracted with dichloromethane (I ml) and the combined organic layers were dried (sodium sulfate) and concentrated to obtain the diethyl ester [(E)-4-amino-2-butene-1-yl]phosphinic acid (5.32 g, 25 mmol); this material was dissolved in ethanol (100 ml) was added for 1.5 h in an ethanol solution (100 ml) of 3,4-diethoxy-3-cyclobutene-1,2-dione (4,32 g, 25.4 mmol). After standing overnight the reaction mixture was concentrated and subjected to purification by means of operation the ester [(E)-4-[(2-ethoxy-3,4-dioxo-1-cyclobutene-1-yl)amino]-2-butenyl] phosphinic acid in the form of a light yellow oil (7,15 g, 85%);

1H-NMR (DCl3, 200 MHz): 6,5 (broad singlet, NH), 5,75-5,66 (multiplet, 2H), 4,77 (Quartet, J=7 Hz, 2H), 4,23 (broad singlet, 2H), 4,2-4,0 (multiplet, 4H), 2,61 (doublet of doublets, J=22 and 7 Hz, 2H), 1,46 (triplet, J=7 Hz, 3H), 1,33 (triplet, J=7 Hz, 6N).

An ethanol solution of ammonia (235 ml) was combined with diethyl ether complex [(E)-4-[(2-ethoxy-3,4-dioxo-1-cyclobutene-1-yl)amino] -2-butenyl] phosphinic acid (7,15 g, 21.6 mmol) and the solution was stirred for 3 days and then evaporated. As a result of recrystallization from methanol in ethyl acetate was removed yellow impurity, but operational chromatography (7.5 cm diameter, elution with 5% methanol in dichloromethane) was required in order to exclude the more polar impurities. After recrystallization of this material from methanol in ethyl acetate (final volume 200 ml) was received diethyl ester [(E)-4-[2-amino-3,4, dioxo-1-cyclobutene-1-yl)amino]-2-butenyl]alkylphosphines acid in the form of chapeaurouge solids (4,43 g, 68% melting point 145-147aboutC).

IR (KBR, cm-1): 3280, 3100, 1800, 1640; MS (+FAB): 303 (MN+, 100), 135 (62).

1H-NMR (DMSO, 400 MHz): 7,5 (broad singlet, NH 3), 5,74-5,68 (multiplet, 1H), 5,57-5,48 (multiplet, 1H), 4.09 to (broad singlet, 2H), was 4.02-3,91 (multiplet, 4H), 2,64 (doubleN2O5P

Found, C To 47.46; H 5,95; N Of 9.21.

A solution of diethyl ether complex [(E)-4-[(2-amino-3,4-dioxo-1-cyclobutene-1 - yl)amino] -2-butenyl] phosphinic acid (1.0 g, 3.3 mmole) and bromotrimethylsilane (4.6 ml, 35 mmol) in anhydrous 1,2-dichloroethane (30 ml) under nitrogen atmosphere was subjected to reflux distilled 20 min, then cooled and evaporated. The residue was dissolved in water (150 ml) and washed with diethyl simple ether (CH ml). The resulting material after concentration of the aqueous layer was subjected to recrystallization from methanol in ethyl acetate (final volume 100 ml) to obtain [(E)-4-[(2-amino-3,4-dioxo-1-cyclobutene-1-yl)amino]-2-butenyl] foshi - new acid, one third hydrate in the form of a yellow solid (0,59 g, 71% melting point 220-230aboutWith (Razlog.)).

IR (KBR, cm-1): 3280, 3100, 1800, 1640; MS (-FAB): 245 (M-H)

1H-NMR (DMSO, 400 MHz): 7,47 (broad singlet, 3NH), 5,63-5,58 (multiplet, 2H), 4,10 (broad singlet, 2H), 2,38 (doublet of doublets, J=21 and 6 Hz, 2H).

Calculated With 38,11; N. Of 4.66; N Is 11.11.

WITH8H11N2O5P 1/3 H2ABOUT

Found, With 38,10; N To 4.46; N 11,00.

P R I m e R 6. [2-[(2-Amino-3,4-dioxo-1-cyclobutene-1-yl)methylamino] ethyl]foshi-new acid.

A cold (0aboutaboutC. the Crude material was subjected to purification using operational chromatography (7.5 cm diameter, elution with 2.5% methanol in dichloromethane) to obtain the diethyl ester of [2-[(2-ethoxy-3,4-dioxo-1-cyclobutene-1-yl)methylamino]ethyl]alkylphosphines acid in the form of oil (3.00 g, 89%).

IR (pure, cm-1IN 1805, 1715, 1620; MS (+FAB): 320 (MH+, 100), 109 (20).

1H-NMR (Dl3, 400 MHz): 4,78-4,74 (multiplet, 2H), 4,16-4.09 to (multiplet, 2H), 4,16-4.09 to (multiplet, 4H), 3,94, 3,68 (multiplet, 2H), 3,35, 3,19 (singlet, 3H), 2,15-2,09 (multiplet, 2H), 1,48-1,44 (multiplet, 3H), 1,34 (triplet, J=7 Hz, 6N).

An ethanol solution (40 ml) diethyl ether complex [2-[(2-ethoxy-3,4-dioxo-1-cyclobutene-1-yl)methylamino] ethyl] Vospi new acid (3.00 g, 9,40 mmol) was combined with ethanol solution of ammonia (70 ml) and was kept for 18 hours After concentrating on the ml) to obtain the diethyl ester of [2-[(2-amino-3,4-dioxo-1-cyclobutene-1-yl)methylamino] ethyl] alkylphosphine - howl acid as a solid (2.10 g, 77% melting point 130-132aboutC).

IR (KBR, cm-1): 3320, 3160, 1800, 1670, 1650, 1640; MS (+FAB): 291 (MN+, 100), 196 (22), 109 (20).

1H-NMR (DMSO, 400 MHz): to 7.61 (broad singlet, NH2), was 4.02-3,94 (multiplet, 4H), 3,74 (broad singlet, 2H), 3,13 (broad singlet, 3H), 2.13 and (doublet of triplets, J=18 and 7.5 Hz, 2H), 1,22 (triplet, J=7 Hz, 6N).

Calculated With 45,52; N 6,60; N 9,65.

WITH11H19N2ABOUT5P

Found, 45,41; N 6,55; N 9,65.

A suspension of diethyl ether complex [2-[(2-amino-3,4-dioxo-1-cyclobutene-1-yl)methylamino]ethyl]phosphinic acid (660 mg, 2.3 mmol) in anhydrous 1,2-dichloroethane (20 ml) under nitrogen atmosphere was treated with bromotrimethylsilane (2.0 ml, 15 mmol) was heated to reflux distilled at 10 minutes, the Yellow solution was concentrated and the resulting solid was dissolved in water (75 ml), washed with diethyl simple ether (CH ml) and evaporated. The solid was dissolved in boiling methanol, filtered and concentrated adding ethyl acetate to a final volume of 75 ml, to obtain a connection from the header of the example CVG, cm-1): 3340, 1800; MS (-FA): 233 (M-N, 32), 148 (100);1H-NMR (DMSO, 400 MHz): 7,62 (broad singlet, NH2), 3,68 (broad singlet, 2H), and 3.16 (broad singlet, 3H), 1,90 (doublet of triplets, J=18 and 7.5 Hz, 2H).

Calculated With 35,91; N 4,74; N 11,96.

WITH7H11N2ABOUT5P

Found, 35,52; N 4,79; N 11,83.

a) Following the procedure in example 6, except that the diethyl ester aminomethylphosphonic acid used as the starting reagent was obtained [[(2-amino-3,4-dioxo-1-cyclobutene-1-yl)methylamino] methyl]foshi - new acid, melting point 245-250aboutWith (Razlog.).

Calculated C 32,74; N 4,12; N Of 12.73.

WITH6H9N2O5P

Found, 32,62; N 4,15; N 12,87.

P R I m e R 7. [2-(7,8-dioxo-2,5-diazabicyclo[4,2,0]Oct-1(6)-EN-2-yl)ethyl]phosphonic acid.

The solution phenylmethylene of ester (2-amino-ethyl)carbamino acid (a 3.06 g, 16 mmol), diethyl ether complex (2-oxoethyl)alkylphosphines acid (2,88 g, 16 mmol) and cyanoborohydride sodium (1,00 g, 16 mmol) in dry methanol (90 ml) was obtained in nitrogen atmosphere. A methanol solution of hydrogen chloride was added to until the solution is slightly acidic (pH 6.5). After 3 h of workesley to a pH of 1.5 using concentrated hydrochloric acid, the methanol was removed under vacuum, and the residue was diluted with water (25 ml). After washing diethyl simple ether (CH ml) the aqueous layer was podslushivaet to pH 10 with 1 n solution of hydroxide of sodium, saturated with solid sodium chloride, and then was extracted with chloroform (CH ml). The dried (sodium sulfate) organic layer was previously adsorbing on silica gel and subjected to purification using operational chromatography (3 cm diameter, gradient elution with 5-10% methanol in dichloromethane) to obtain fenilmetilovy ester [2-[[2-diethoxyphosphoryl)ethyl]amino]ethyl] carbamino acid in the form of a pale yellow oil (2,90 g, 51%),

IR (pure, cm-1): 3300, 1715; MS (+FAB): 359 (MH+, 100), 91 (70).

1H-NMR (Dl3, 400 MHz): of 7.36 (multiplet, 5H), 5,46 (broad singlet, NH), 5,10 (singlet, 2H), 4,16-was 4.02 (multiplet, 4H), 3,29 (Quartet, J=5.5 Hz, 2H), 2,89 (doublet of triplets, J=17 and 7 Hz, 2H) triplet, J=5.5 Hz, 2H), 1,95 (doublet of triplets, J=18 and 7 Hz, 2H), 1,82 (broad singlet, NH), 1,31 (triplet, J=7 Hz, 6N).

Calculated, 51,55; N 7,73; N 7,51.

WITH16H27N2O5P 4/5 H2ABOUT

Found, 51,69; N 7,83; N 7,53.

Into a flask containing 10% palladium on carbon (3,79 g) in a nitrogen atmosphere, was added fenilmetilovy ester [2-[[2-(diethoxyphosphoryl, 110 mmol). After stirring the suspension overnight, the mixture was filtered through Celite, was previously adsorbing onto silica gel and subjected to purification using operational chromatography (7 cm diameter, elution dried (magnesium sulfate) 5 (10) 85 hydroxide ammonium (methanol/dichloromethane) to obtain the diethyl ester of [2=[(2-amino-ethyl)amino]ethyl]alkylphosphines acid as a yellow oil (1.98 g, 88% ); MS (+FAB): 225 (MN+, 9), 194 (100), 166(34), 138(71), 120(38), 57(39), 44(32).

1H-NMR (CDCl3, 400 MHz): 4,18-4,04 (multiplet, 4H), 2.91 in (doublet of triplets, J=15 and 7 Hz, 2H), 2,80 (triplet, J=5.5 Hz, 2H), 2,68 (triplet, J=5.5 Hz, 2H), 1,98 (doublet of triplets, J=18 and 7 Hz, 2H), 1,68 (broad singlet, NH 3), 1,33 (triplet, J=7 Hz, 6N).

Solutions (10 ml each) of 3,4-diethoxy-3-cyclobutene-1,2-dione (1,27 ml, 8.6 mmol) and diethyl ether complex [2-[(2-amino-ethyl/amino]ethyl]alkyloxy new acid (1.92 g, 8.6 mmol) in ethanol was separately injected through a syringe into deleverage ethanol (22 ml) for 3 hours After reflux distilled during the night the red-brown solution was previously adsorbing on silica gel and subjected to purification using operational chromatography (7 cm diameter, gradient elution with 2.5-10% methanol in ethyl acetate) and podelko[4,2,0]Oct-1(6)-EN-2-yl/ethyl]phosphinic acid in the form of a beige solid (0,78 g, 30% of the melting point 115-116aboutC).

IR (KBR, cm-1): 3170, 1780, 1660; MS (+FAB): 303 (MH+, 100), 109 (38).

1H-NMR (DCl3, 400 MHz): to 7.64 (broad singlet, NH), 4,16-4,06 (multiplet, 4H), 3,80-to 3.73 (multiplet, 2H), 3,63-3,60 (multiplet, 2H), 3,48 (triplet, J=5 Hz, 2H), 2,31 (doublet of triplets, J=18 and 7.5 Hz, 2H), 1,33 (triplet, J=7 Hz, 6N).

Calculated With 47,68; N 6,34; N 9,27.

WITH12H19N2O5P

Found,47,39; N 6,32; N WHICH 9.22

A solution of ester diethyl [2-(7,8-dioxo-2,5-diazabicyclo[4.2.0] OCTA-1(6)-EN-2-yl)ethyl] phosphinic acid (0,78 g, 2.6 mmol) and bromotrimethylsilane (2.1 ml, 16 mmol) in dry 1,2-dichloroethane (30 ml) was subjected to reflux distilled in nitrogen for 20 minutes the Cooled reaction mixture was concentrated under vacuum and the residue was dissolved in water (100 ml) and washed with diethyl simple ether (CH ml). After concentration of the aqueous layer, the residue was subjected to recrystallization from water (25 ml) and methanol (300 ml) to obtain a beige solid impurities which were removed by filtration. The filtrate was concentrated and subjected to recrystallization from water in isopropanol, to obtain a connection from the header of the example as a yellow solid (0,37 g, 58% melting point 220-270aboutthe 3,40-3,33 (multiplet, 4H), 2,07-1,98 (multiplet, 2H).

Calculated With 39,04; N 4,50; N 11,38.

WITH8H11N2O5P

Found, 38,60; N 4,30; N Is 11.11.

P R I m e R 8. [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-EN-2-yl)ethyl]phosphinic acid.

The solution phenylmethylene of ester (3-aminopropyl)carbamino acid (6.11 g, 29 mmol), diethyl ether complex (2-oxoethyl)alkylphosphines acid (5,24 g, 29 mmol) and cyanoborohydride sodium (2,73 g, 43 mmol) in dry methanol (100 ml) was obtained in nitrogen atmosphere. A methanol solution of hydrogen chloride was added until, until the solution remained slightly acidic (pH 6.5). After several hours the reaction was maintained acidic (pH of 1.5) using concentrated hydrochloric acid, the methanol was removed under vacuum and the residue was diluted with water (25 ml). After washing diethyl simple ether (CH ml) the aqueous layer was podslushivaet to pH 10 using 10 N. solution of the hydroxide of sodium, saturated with solid sodium chloride, and then was extracted with chloroform (CH ml). The dried (sodium sulfate) organic layer was previously adsorbing on silica gel and subjected to purification using operational chromatography (7 cm diameter, gradient Elul]amino] Pro-MPI] carbamino acid in the form of a waxy solid (3,86 g, 36%),

IR (pure, cm-1): 3300, 1720, 1250, 1030; MS (+FAB): 373 (MN+, 100), 91(90).

1H-NMR (DCl3, 400 MHz): of 7.36-7.29 trend (multiplet, 5H), to 5.58 (broad singlet, NH), 5,09 (singlet, 2H), 4,15-4,04 (multiplet, 4H), 3,29 (Quartet, J=6 Hz, 2H), 2.91 in (doublet of triplets, J=16 and 7 Hz, 2H), 2,71 triplet, J=6 Hz, 2H), 1,98 (doublet of triplets, J=18 and 7 Hz, 2H), 1,70 (pentec, J=6 Hz, 2H), 1,31 (triplet, J=7 Hz, 6N).

The solution phenylmethylene of ester [3-[[2-diethoxyphosphoryl/ethyl]amino]propyl]carbamino acid (3,17 g, 8.5 mmol) in absolute ethanol (40 ml) was added over 45 minutes 3.4-diethoxy-3-cyclobutene-1,2-dione (2.3 ml, 16 mmol) dissolved in ethanol (55 ml). After standing overnight the reaction mixture was previously adsorbing on silica gel and subjected to purification using operational chromatography (7 cm diameter, gradient elution with 2.5-10% methanol in dichloromethane) to obtain fenilmetilovy ester [3-[[2-(di-ethoxyphenyl)ethyl](2-ethoxy-3,4-dioxit - loboutin-1-yl)amino]propyl]carbamino acid as a viscous oil (3.75 g, 89% ).

1H-NMR (DCl3, 400 MHz): 7,35 (multiplet, 5H), of 5.45 (broad multiplet, NH), 5,09 (singlet, 2H), 4.80 to 4,71 (multiplet, 2H), 4,16-4.09 to (multiplet, 4H), 3,90-3,48 (multiplet, 4H), 3,23-3,20 (multiplet, 2H), 2,16-2,04 (Uu 10% palladium on carbon (2,11 g), in an atmosphere of nitrogen was added fenilmetilovy ester [3-[[2-(diethoxyphosphoryl)ethyl](2-ethoxy-3,4-di - oxo-1-cyclobutene-1-yl) amino]propyl]carbamino acid (2,11 g, 4.2 mmol) in absolute ethanol (180 ml), then 1,4-cyclohexadiene (4.3 ml, 45 mmol). After stirring for 5 h the reaction mixture was filtered through Celite and concentrated under vacuum to get crude solid, which was subjected to recrystallization from methanol and ethyl acetate (total volume 20 ml), was filtered and washed with hexane to obtain hemihydrate diethyl ether complex [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0] non-1(7)-EN-2-yl)ethyl] phosphinic acid in the form of a cream solid color (0,82 g, 62% melting point 148-149aboutC).

IR (KBR, cm-1): 1810.

1H-NMR (Dl3, 400 MHz): 7,50 (broad singlet, NH), 4,18-4,10 (multiplet, 4H), 4.09 to 4,00 (multiplet, 2H), 3,51-of 3.46 (multiplet, 4H), 2,19 (doublet of triplets, J=18 and 7.5 Hz, 2H), 2,10-2,04 (multiplet, 2H), 1,34 (triplet, J=7 Hz, 6N).

Calculated With 47,99; N 6,82; N 8,61.

WITH13H21N2O5P 1/2 H2O

Found, 48,23; N To 6.57; N Charged 8.52.

A solution of ester diethyl [2-(8,9-dioxo-2,6-diazabicyclo[5,2,0] non-1(7)-EN-2-yl)ethyl] Postanovlenie 20 min in nitrogen atmosphere. The cooled reaction mixture was concentrated under vacuum, and the residue was dissolved in water (100 ml) and washed with diethyl simple ether (CH ml). Water was removed under vacuum and the resulting solid was subjected to recrystallization from water and isopropanol to obtain [2-(8,9-dioxo-2,6-diazabicyclo[5,2,0]-non-1/7-EN-2-yl/ /ethyl] phosphinic acid, one-fifth of the hydrate in the form of a yellow solid (0,91 g, 78% melting point 260-278aboutWith, (Razlog.).

IR (KBR, cm-1): 1800.

1H-NMR (DMSO, and 1 drop of DCl, 400 MHz): 3,85-3,79 (multiplet, 2H), 3,35-3,32 (multiplet, 2H), 3.25 to 3,23 (multiplet, 2H), 1,97-1,87 (multiplet, 4H).

Calculated With 40,98; N 5,12; N 10, 68.

WITH9H13N2ABOUT5R 1/5 H2ABOUT

Found, 40,98; N To 4.98; N 10,38.

P R I m e R 9. [2-(4-hydroxy-8,9-dioxo-2,6-diazabicyclo[5,2,0]non-1(7)-EN-2-yl)ethyl]FOS - finova acid.

A solution of 1,3-diamino-2-oxypropane (27,0 g, 0,300 moles) in dry acetonitrile (270 ml) was maintained at ambient temperature in a water bath and was treated with di-tert-butyl dicarbonate (23,0 ml, 0,100 mol) in acetonitrile (90 ml) for 2 h with vigorous mechanical stirring, and then stood overnight. The reaction mixture was concentrate is Yan. The mixture was treated with 1 N. a solution of hydrochloric acid until then, until it will turn into yellow, washed with dichloromethane (3x250 ml) and then made alkaline (pH 12) by the addition of 2.5 n solution of hydrate of sodium oxide. The product was extracted into chloroform (CH ml), dried with sodium sulfate and concentrated to obtain 1,1-dimethylethylene ester (3-amino-2-oksipropil)carbamino acid as a white solid (7,76 g, 41% of the melting point 77-79aboutC).

IR (KBR, cm-1): 3360, 1680, MS (+FA): 191 (MN+, 42), 135 (100), 58 (78).

1H-NMR (DCl3, 400 MHz): 5,04 (broad singlet, NH), 3,65-3,60 (multiplet, 1H), 3,34-3,22 (multiplet, 1H), 3,12-3,05 (multiplet, 1H), 2,83 (doublet of doublets, J=13 and 4 Hz, 1H), 2.63 in (doublet of doublets, J=13 and 7.5 Hz, 1H), 1,44 (singlet, N).

A solution of 1,1-dimethylethylene of ester (3-amino-2-oksipropil)carbamino acid (7,73 g, 41 mmol), sodium carbonate (6,52 g, 62 mmole) and diethyl 2-bromatological (11.8 ml, 65 mmol) in absolute ethanol (150 ml) was obtained in nitrogen atmosphere. The mixture was subjected to reflux distilled during the night, and then concentrated under vacuum. The residue was dissolved in chloroform (150 ml), and then was previously adsorbing on silica gel and subject - Ghali PTS is Tanya, to obtain 1,1-dimethylethylene ester [3-[[2-(diethoxyphosphoryl) ethyl]amino]-2-oksipropil]carbamino KIS lots in the form of a colorless oil (11,16 g, 77%).

IR (pure, cm-1): 3320, 1710, 1250, 1170, 1040; MS (+FAB): 355 (MH+, 68), 255 (90), 58 (100).

1H-NMR (Dl3, 400 MHz): 5,23 (broad singlet, NH), 4,16-4,05 (multiplet, 4H), of 3.77 (multiplet, 1H), 3,32-2,90 (multiplet, 4H), 2,73 (doublet of doublets, J=12, 3.5 Hz, 1H), 2,58 (doublet of doublets, J=12 and 8.5 Hz, 1H), 2.00 (doublet of triplets, J= 18 and 7 Hz, 2H), 1,43 (singlet, N), 1,32 (triplet, J=7 Hz, 6N).

To a solution of 3,4-diethoxy-3-cyclobutene-1,2-dione (5.0 ml, 34 mmole) in absolute ethanol (180 ml) obtained in nitrogen atmosphere, was added a solution of 1,1-dimethylethylene of ester [3-[[2-(diethoxyphosphoryl)ethyl]amino]-2-oksipropil] carbamino acid (12,11 g, 34 mmole) in ethanol (60 ml) for 1 h, the Reaction mixture was stirred at room temperature overnight, and then concentrated under vacuum. The residue was dissolved in chloroform (150 ml), was previously adsorbing on silica gel and subjected to purification using operational chromatography (7 cm diameter, gradient elution with 2.5-15% methanol in dichloromethane) to obtain 1.1-dimethylethylamine ester [3-[[2-(diethoxyphosphoryl)ethyl](2-ethoxy-3,4-di-the ptx2">

IR (pure, cm-1): 3350, 1800, 1700.

1H-NMR (DCl3, 400 MHz): lower than the 5.37, 5,19 (broad singlet, NH), 4,82-4,72 (multiplet, 3H), 4,16-3,11 (multiplet, 11N), 2,24-2,14 (multiplet, 2H), 1,47-1,43 (multiplet N), 1,32 (triplet, J=7 Hz, 6N).

A solution of 1,1-dimethylethylene of ester [3-[[2-diethoxyphosphoryl)ethyl] (2-ethoxy-3,4-dioxo-1-cyclobutene-1-yl)AMI-but] -2-oksipropil]carbamino acid (11,34 g, 24 mmole) in 96% formic acid (100 ml) was obtained in nitrogen atmosphere and stirred at room temperature overnight. The reaction mixture was then concentrated under vacuum to obtain a yellow sticky oil, which was dissolved in absolute ethanol (120 ml) and was added dropwise over 1.5 h to a solution of diisopropylethylamine (16,7 ml, 96 mmol) in absolute ethanol (360 ml). After reflux distilled over night the reaction mixture was concentrated under vacuum, and the residue was dissolved in chloroform (150 ml), was previously adsorbing on silica gel, and subjected to purification using operational chromatography (9 cm diameter, gradient elution 5-20% methanol in dichloromethane) to obtain the diethyl ester of [2-(4-hydroxy-8,9-dioxo-2,6-diazabicyclo[5,2,0]non-1(7)-EN-2-yl/ethyl]phosphine th acid as a white solid (5,94 g, 74% the, 00), 185 (50), 179 (78).

1H-NMR (DCl3, 400 MHz): 7,18 (broad singlet, NH), to 4.52-of 4.44 (multiplet, 1H), 4,20 (multiplet, 1H), 4,14-4,04 (multiplet, 4H), 3,79-3,70 (multiplet, 2H), 3,57-3,54 (multiplet, 2H), 3,36 (doublet, J=14 Hz, 1H), 2,33-2,13 (multiplet, 2H), 1,32 (doublet of triplets, J=13 and 7 Hz, 6N).

Calculated With 46,89; N 6,37; N 8,43.

WITH13H21N2O6P

Found, With 47,07; N 6,11; N Of 8.37.

To a solution of ester diethyl [2-(4-hydroxy-8,9-dioxo-2,6-diazabicyclo[5,2,0] non-1(7)-EN-2-yl)ethyl]phosphinic acid (2.5 g, 7.5 mmol) in dry 1,2-dichloromethane (100 ml) under nitrogen atmosphere was added bromotrimethylsilane (9,2 ml, 60 mmol). The reaction mixture was subjected to reflux distilled 20 min, and then concentrated under vacuum to obtain a yellow-orange foam, which was dissolved in water (100 ml). The water washed the simple ether (CH ml) and then concentrated under vacuum to obtain solid, which was subjected to recrystallization from water in isopropanol to obtain [2-(4-hydroxy-8,9-dioxo-2,6-diazabicyclo[5,2,0] -non-1(7)-EN-2-yl)ethyl]phosphinic acid, one-sixth hydrate in the form of a pale yellow solid (1,79 g, 86% melting point 268-270aboutWith Razlog.).

IR (KBR, cm-1): 3480, 3220, 1820; MS (-FAB): 275 (M-H, 22), 1 1H), 3,34 (doublet of doublets, J=13 and 7 Hz, 1H), 3,28 (multiplet, 2H), 1,98-1,89 (multiplet, 2H).

Calculated C 38,72; N To 4.81; N There Is A 10.03.

WITH9H13N2O6P 1/6 H2O

Found, 38,46; N 4,59; N There Is A 10.03.

a) Following the procedure of example 9, except that 2,2-dimethyl-1,3-propandiamine used as a reagent was obtained [2-(4,4-dimethyl-8,9-dioxo-2,6-diazabicyclo[5,2,0] non-1(7)-EN-2-yl)ethyl] phosphinic acid, monohydrate, melting point 265-282aboutWith (Razlog.).

Calculated With 43,14; N. Of 6.25; N 9,15.

WITH11H17N2O5P H2ABOUT

Found, 42,98; N 6,04; N 9,02.

b) Following the procedure of example 9, except that 1,3-propandiamine and diethyl 3-bromopropionate are reagents were obtained [3-(8,9-dioxo-2,6-diazabicyclo[5,2,0] non-1-(7)-EN-2-yl)propyl] phosphinic acid, melting point 244-248aboutC.

Calculated With 43,93; N 5,42; N 10,18.

WITH10H15N2O5P

Found, 43,93; N 5,42; N 10,18.

(C) Following the procedure of example 9, except that 1,3-propandiamine and diethyl (E)-(3-chloro-1-propenyl)phosphonate reagents are received [(E)-3-(8,9-dioxo-2,6-diazabicyclo[5,2,0]non-1(7)-EN-2-yl)-1-propenyl]Vospi Novak,88; N 10,18.

WITH10H13N2O5P 1/6 H2O.

Found, C 43,69; N To 4.68; N 10,02.

P R I m e R 10. 8,9-Dioxo-2,6-diazabicyclo[5,2,0]non-1(7)-EN-2-acetic acid.

The solution phenylmethylene of ester (3-aminopropyl)carbamino acid (7,08 g, 34 mmol) and N,N-diisopropylethylamine (4,5 ml, 26 mmol) in anhydrous dimethylformamide (100 ml) under nitrogen atmosphere was cooled to 10aboutAnd was treated with tert-butyl bromoacetate (2,80 ml, 17 mmol) for 5 minutes After 1 h bath was removed and the reaction mixture was stirred overnight, poured into water (500 ml) and made alkaline (pH 12) of 2.5 N. the solution of hydrate of sodium oxide. The aqueous layer was extracted with dichloromethane (2x250 ml), dried over sodium sulfate and concentrated under vacuum while heating to remove dimethylformamide. The residue was subjected to purification using operational chromatography (9 cm diameter, gradient elution of 2.5-3.5% methanol in dichloromethane) to obtain fenilmetilovy ester [3-[[(1,1-dimethylthiocarbamyl)methyl] amino] Pro - MPI]carbamino acid in the form of a pale yellow oil (4,50 g, 82%).

1H-NMR (DCl3, 200 MHz): 7,35 (multiplet, 5H), 5,43 (broad singlet, NH), 5,09 (singlet, 2H), 3,35-3,24 (minimetro of ester [3-[[(1,1-dimethylthiocarbamyl/methyl] amino] propyl]carb - mirovoy acid (4,49 g, 13.9 mmol) under nitrogen atmosphere was added 3,4-diethoxy-3-cyclobutene-1,2-dione (2.0 ml, 13 mmol) in the same solvent (60 ml) for 1 h Later for an additional 3.5 h, the reaction mixture was previously adsorbing on silica gel and subjected to purification using operational chromatography (7.5 cm diameter, gradient elution 30-60% ethyl acetate in petroleum ether) to obtain fenilmetilovy ester [3-[[(1,1-dimethylthiocarbamyl)methyl]-(2 ethoxy-2,4-dioxo-1-cyclobutene - 1-yl)amino]propyl]carbamino acid as a viscous colorless oil (5,26 g, 91%); MS (+CL): 447 (MH+, 100), 391 (38).

1H-NMR (Dl3, 400 MHz): 7,35 (multiplet, 5H), 5,55, equal to 4.97 (broad multiplet, NH), 5,10 (singlet, 2H), 4.75 in, 4,73 (Quartet, J=7 Hz, 2H), 4,29, 3,99 (singlet, 2H), 3,74, 3,49 (triplet, J=6.5 Hz, 2H), 3,29-3,22 (multiplet, 2H), 1,84-1,75 (multiplet, 2H), 1,48, 1,47 (singlet, N), 1,45-1,40 (multiplet, 3H).

Into a cooled flask (20about(C) containing 10% palladium on carbon (5,25 g) in a nitrogen atmosphere, was added fenilmetilovy ester [3-[[(1,1-dimethylthiocarbamyl)methyl]-(2-ethoxy-3,4-dioxo-1-cyclobutene - 1-yl)amino]propyl] carbamino acid (5,25 g, 11.8 mmol) in ethanol (500 ml), then 1,4-cyclohexadiene (11 ml, 0.12 moles) within 5 minutes After 5 h, the suspension was filtered through Qi purification using operational chromatography (7.5 cm diameter, gradient elution with 2.5-3% methanol in dichloromethane) to obtain 1.1-dimethylethylamine ester (8,9-dioxo-2,6-diazabicyclo[5,2,0]non-1(7)-EN-2-yl)- acetic acid as a white solid (2,59 g, 82% melting point 167-168aboutC).

IR (KBR, cm-1): 3200, 1800, 1720; MS (E1): 266 (M+, 42), 210 (33), 166 (37), 165 (100), 154 (58), 138 (37), 70 (58).

1H-NMR (DMSO, 400 MHz): to 8.62 (broad singlet, NH), of 4.38 (singlet, 2H), 3,36-3,27 (multiplet, 4H), 1.91 a (multiplet, 2H), 1,40 (singlet, N).

Calculated C 58,63; N For 6.81; N 10,52.

WITH13H18N2O4< / BR>
Found, With 58,57; N Is 6.78; N The 10.40.

Ethanol (86 ml) solution of 1,1-dimethylethylene of ester (8,9-dioxo-2,6-diazabicyclo[5,2,0] non-1(7)-EN-2-yl[vinegar - Noah acid) (to 2.29 g, at 8.60 mmol) was treated at room temperature for 2.5 N. the solution of hydrate of sodium oxide (3.5 ml, 8.7 mmol) and was stirred over night. The suspension was filtered, washed with ethyl acetate to obtain a solid, which was subjected to recrystallization from methanol (water) isopropanol (final volume 50 ml), to obtain the salt hydrate of sodium (8,9-dioxo-2,6-diazabicyclo[5,2,0]non-1(7)-EN-2-yl)acetic acid (1,43 g, 66% melting point 280-300aboutWith Razlog.); MS (-FAB): 231 (M-N is o, 2H).

Calculated With 43,21; N 4,43; N 11,20.

WITH9H9N2NaO4H2O

Found, 43,29; N. Of 4.38; N 11,32.

a) Following the procedure of example 10, except that ethyl 3-bromopropionate used as a reagent, received half hydrate sodium salt 3-(8,9-dioxo-2,6-diazabicyclo[5,2,0]non-1(7)-EN-2-yl]propanoic acid, melting point 310aboutWith (Razlog.).

Calculated With 44,04; N 4,99; N 10,27.

WITH10H11N2NaO41,5 H2ABOUT

Found, 44,28; H 5,15; N 10,24.

P R I m e R 11. 2-[(1H-tetrazol-5-yl)methyl]-2,6-diazabicyclo[5,2,0] non-1(7)-ene-8,9 - dione

A solution of 1,1-dimethylethylene of ester (3-aminopropyl)carbamino acid (6,00 g, 34 mmol), obtained using the procedure Saari and other J. Med.Chem. so 33, page 97 (1990), in absolute ethanol (90 ml), treated with sodium carbonate (3,96 g, 37 mmol), then the solution bromoacetonitrile (2,6 ml, 37 mmol) in ethanol (30 ml) for 45 minutes After stirring at room temperature during the night the contents of the flask were filtered, was previously adsorbing on silica gel and subjected to purification using operational chromatography (7 cm diameter, elution with 2.5% methanol in dichloromethane), what about the oil (3,99 g, 55%).

IR (pure, cm-1): 3330, 2240, 1700; MS (+CL): 214 (MN+, 20), 187 (76), 158 (100), 131 (44).

1H-NMR (DCl3, 400 MHz): 4,80 (broad singlet, NH), 3,61 (singlet, 2H), 3,22 (Quartet, J= 6.5 Hz, 2H), 2,79 (triplet, J=6.5 Hz, 2H), 1.69 in (pentec, J=6,5 Hz, 2H), 1,45 (singlet, N).

A solution of 3,4-diethoxy-3-cyclobutene-1,2-dione (2.6 ml, 18 mmol) in absolute ethanol (90 ml) was treated with 1,1-dimethylethylamine complex ester [3-(cyanomethylene)propyl] carbamino acid (3,90 g, 18 mmol) in ethanol (30 ml) for 90 minutes After 40 h, the reaction mixture was evaporated, dissolved in dichloromethane, was previously adsorbing onto silica gel and subjected to purification using operational chromatography (7 cm diameter, gradient elution 0-5% methanol in dichloromethane), to obtain 1,1-dimethylethylene ester [3-[(cyanomethyl)-(2-ethoxy-3,4-dioxo-1-cyclobutene-1-yl)amino]propyl]the carbs novacolor in the form of a yellow oil (5,48 g, 90%).

IR (pure, cm-1): 3360, 1800; MS (+FAB): 282 (76), 238 (98), 158 (100),

1H-NMR (Dl3, 400 MHz): 4,81 (Quartet, J=7 Hz, 2H), and 4.75 (broad singlet, NH), 4,45, 3,66 (singlet, 2H), 3,84, of 3.60 (broad multiplet, 2H), 3,26-3,15 (multiplet, 2H), 1.91 a (pentec, J=6,5 Hz, 2H), 1,50 (triplet, J=7 Hz, 3H), 1,45 (singlet, N).

A solution of 1,1-dimethylethylamine) in 96% formic acid (40 ml) was obtained in nitrogen atmosphere. After 24 h the solvent was removed, and the residue was dissolved in isopropanol and concentrated several times. Added ethanol (40 ml) and the suspension was stirred overnight, then filtered to obtain (8,9-dioxo-2,6-diazabicyclo[5,2,0]-non-1(7)-EN-2-yl)acetonitrile, one-eighth hydrate as a white solid (1.50 g, 48% melting point 213-218aboutC).

IR (KBR, cm-1): 3220, 1810; MS (DEI): 191 (M+, 57), 135 (41), 70 (41), 43 (70), 41 (100).

1H-NMR (DMSO, 400 MHz): 8,83 (broad singlet, NH), 4,84 (singlet, 2H), 3,40-3,30 (multiplet, 4H), 1,95 (multiplet, 2H).

Calculated 55,93; N 4,69; N 21,74.

WITH9H9N3O21/8 H2O

Found, 55,99; N Was 4.76; N 21,90.

In solution (8,9-dioxo-2,6-diazabicyclo[5,2,0]non-1(7)-EN-2-yl)acetonitrile, one-eighth hydrate (1.54 g, 8.0 mmol) in dry dimethylformamide (35 ml) under nitrogen atmosphere was added sodium azide (0,79 g, 12 mmol) and ammonium chloride (0.65 g, 12 mmol). The reaction mixture was slowly heated to 125aboutC, maintained at this temperature for 2 hours, cooled to room temperature, and then filtered. The concentrated filtrate was dissolved in water and evaporated. The residue was subjected to recrystallization from methanol to obtain 2-[(1H-tetrazol-mperature the melting point 264-267aboutC).

IR (KBR, cm-1): 3200, 1810;1H-NMR (DMSO, 400 MHz): 8,70 (singlet, NH), 5,24 (singlet, 2H), 3,34 of 3.28 (multiplet, 4H), 1,92 (multiplet, 2H).

Calculated From 45.00; H 4,48; N 34,98.

WITH9H10N6O21/3 H2O

Found, 45,28; N Is 4.21; N 34,76.

a) Following the procedure of example 11 with the exception that 3-bromopropionitrile used as a reagent was obtained 2-[2-(1H-tetrazol-5-yl)ethyl] -2,6-disabil - CLO[5,2,0] non-1(7)-ene-8,9-dione, melting point 255-262aboutC (decomposition).

Calculated, 48.38 Per; N To 4.87; N 33,85.

WITH10H12N6ABOUT2< / BR>
Found, 48.10 Per; N 4,80; N 34,19.

P R I m e R 12. [2-(9,10-Dioxo-2,7-diazabicyclo[6,2,0]Oct-1(8)-EN-2-yl)ethyl]foshi-new acid.

A solution of 1,4-diaminobutane (30 ml of 0.30 mol) in dry tetrahydrofuran (90 ml) maintained at 0aboutAnd was treated with di-tert-butyl dicarbonate (23 ml of 0.10 mol) in tetrahydrofuran (90 ml) for 1.5 h with vigorous mekhanicheskom stirring, and then stood overnight. The reaction mixture was concentrated under vacuum and the residue was dissolved in water (100 ml) to which was added bromcresol greens. This mixture was treated with 1 N. a solution of hydrochloric sour the ri means of adding a 2.5 n solution of hydrate of sodium oxide. The product was extracted into chloroform (CH ml), dried with sodium sulfate and concentrated to obtain 1,1-dimethylethylene ester (4-aminobutyl)carbamino acid as a yellow oil (13,4 g, 71%).

IR (pure, cm-1): 3350; 1700; MS (E1): 188 (M+, 4), 132 (56), 115 (33), 70 (100).

1H-NMR (Dl3, 400 MHz): value of 4.76 (broad singlet, NH), 3,11 (Quartet, J= 6 Hz, 2H), 2,70 (triplet, J=6 Hz, 2H), 1,58-1,45 (multiplet, 4H), 1,43 (singlet, N).

A solution of 1,1-dimethylethylene of ester (4-aminobutyl)carbamino acid (13.3 g, 71 mmol), sodium carbonate (11,25 g, 106 mmol) and diethyl 2-bromo-ethylphosphonate (20 ml, 104 mmol) in absolute ethanol (150 ml) was obtained in nitrogen atmosphere. This mixture was subjected to reflux distilled during the night, and then concentrated under vacuum. The residue was dissolved in chloroform (150 ml), and then was previously adsorbing onto silica gel and subjected to purification using operational chromatography (7 cm diameter, gradient elution 5-30% methanol in dichloromethane) to obtain 1.1-dimethylethylamine ester [4-[[2-(diethoxyphosphoryl)ethyl] amino]butyl]carbamino acid as a colourless oil (13,7 g, 55%); MS (+FAB): 353 (MN+, 100), 150 (68), 56 (83).

1H-NMR (DCl3, 400 MHz): 5,01 (wide blue is 6 (broad triplet, J=7 Hz, 2H), 2,02 (doublet of triplets, J=18 and 7.5 Hz, 2H), 1.56 to 1.52m (multiplet, 4H), 1,43 (singlet, N), 1,33 (triplet, J=7 Hz, 6N).

To a solution of 3,4-diethoxy-3-cyclobutene-1,2-dione (5.8 ml, 39 mmol) in absolute ethanol (200 ml) obtained in nitrogen atmosphere, was added a solution of 1,1-dimethylethylene of ester [4-[[2-(diethoxyphosphoryl)ethyl]amino] butyl] carbamino acid (13,7 g, 39 mmol) in ethanol (75 ml) in a period of 1.75 hours the Reaction mixture was stirred at room temperature overnight, and then concentrated under vacuum. The residue was dissolved in chloroform (150 ml), was previously adsorbing on silica gel and subjected to purification on operational chromatography (9 cm diameter, elution with 2.5% ethanol in dichloromethane) to obtain 1.1-dimethylethylamine ester [4-[[2-(diethoxyphosphoryl)ethyl] (2-ethoxy-3,4-dioxo-1-cyclobutene-1-yl) amino]butyl] carbamino acid as a yellow viscous oil (16,8 g, 90).

A solution of 1,1-dimethylethylene of ester [4-[[2-(diethoxyphosphoryl) ethyl] (2-ethoxy-3,4-dioxo-1-cyclobutene-1-yl)amino] butyl]carbamino acid (16,8 g, 35 mmol) in 96% formic acid (100 ml) was obtained in nitrogen atmosphere and stirred at room temperature overnight. The reaction mixture was then concentrated under in the Yali for 1.5 h in a solution of diisopropylethylamine (17 ml, 98 mmol) in absolute ethanol (375 ml). After reflux distilled over night the reaction mixture was concentrated under vacuum, and the residue was dissolved in chloroform (150 ml), was previously adsorbing on silica gel, and subjected to purification on rapid chromatographic column (9 cm diameter, gradient elution with 5-10% methanol in dichloromethane) to obtain the diethyl ester of [2-(9,10-dioxo-2,7-diazabicyclo[6,2,0] Oct-1(8)-EN-2-yl)ethyl] phosphine - howl acid as a pale yellow solid (9,65 g, 83% the melting point 103-105aboutC).

IR(KBR, cm-1): 3440, 3230, 1795; MS (+FAB): 331 (MH+, 100), 109 (31).

1H-NMR (Dl3, 400 MHz): 7,14 broad singlet, NH), 4,16-4,05 (multiplet, 6N), 3,39-3,36 (multiplet, 4H), 2,17 (doublet of triplets, J=19 and 7.5 Hz, 2H), 1,74-1,68 (multiplet, 4H), 1,33 (triplet, J=7 Hz, 6N).

Calculated With 50,91; N 7,02; N 8,48.

WITH24H23N2O5P

Found, 50,76; N 6,82; N Of 8.37.

To a solution of ester diethyl [2-(9,10-dioxo-2,7-diazabicyclo[6,2,0]Oct - -1(8)-EN-2-yl)ethyl]alkylphosphines acid (7,60 g, 23 mmol) in dry 1,2-dichloroethane (300 ml) under nitrogen atmosphere was added bromotrimethylsilane (25 g, 160 mmol). The reaction mixture was subjected to reflux distilled 25 min, and then to the simple ether (3x250 ml), and then concentrated under vacuum to obtain a yellow-orange solid, which was subjected to recrystallization from water (100 ml) to obtain [2-(9,10-dioxo-2,7-diazabicyclo[6,2,0]Oct-1(8) -EN-2-yl)ethyl]phosphinic acid hydrate in the form of a reddish-brown solid (3.80 g, 60% melting point 266-271aboutWith Razlog.).

IR (KBR, cm-1): 3350, 3260, 1800; MS (-FAB): 273 (M-N).

1H-NMR (DMSO, 400 MHz): 8,32 (broad singlet, NH), 3,94-a 3.87 (multiplet, 2H), 3,31 of 3.28 (multiplet, 2H), 3,22-3,18 (multiplet, 2H), 1,96-1,87 (multiplet, 2H), 1,61-1,49 (multiplet, 4H).

Calculated With 41,10;N 5,86; N 9,59.

WITH10H15N2ABOUT5P H2O

Found, 41,22; N 5,76; N 9,65.

Using procedures similar to the procedures of examples 7 and 8 were obtained the following compounds:

Example Compound 13 [(E)-3-(7,8-dioxo-2,5-

diazabicyclo[4,2,0]Oct-1(6)-

EN-2-yl)-1-propenyl] foshi-

new acid 14 [3-(7,8-dioxo-2,5-

diazabicyclo[4.2.0]Oct-

1(6)-EN-2-yl)propyl]FOS-

finova acid

Have established that the compounds that are the subject of the present invention, are competing the NMDA-antagonists; this was done by determining their ability to inhibit the antagonist, with the NMDA-receptors in the homogenate of brain cells of the rat. Using a procedure analogous to the procedure of the work of Murphy and others, I. Pharmacol. Exp. Therap. so 240 (3), pages 778 (198), homogenates of brain cells, which was previously deleted endogenous glutamate, were incubated with (3H) RAF (8 nm), the compound to be tested, and then the buffer every 15 min at 23aboutTo get a final volume of 2 ml, the Number of radio-ligand demonstrative test the connection, expressed in percent of the radio-ligand, showing the NMDA. Inhibitory concentration of test compounds that will displace 50% of the labeled RAF, was determined from estimates of the type of dose-response.

The properties of these compounds, in addition, established by the confirmation of the properties of the NMDA-antagonist representatives of the compounds on male mice Swiss-albino (strain CD-1, Charles river) weighing 18-22 g after 18 h after feed deprivation, which was placed in the camera for observation for 30 minutes Mice pre-treated with representatives of the test compounds, and then, after thirty minutes, the NMDA (195 mg/kg, intraperitoneal way, U90the dose for the General myoclonus). Then the mice were observed for 30 minutes, locking the IC is givana trunk muscles with loss of reflex rise on his hind legs) and death. From the last determined the ED50for survival. In this standard experimental test procedure was tested specific compounds and their activity, which activities were determined for all compounds listed in the table.

When the displacement of the RAF-binding is expressed as a percent, M is the concentration defined as the concentration in parentheses. Similarly, when the inhibition is indicated in percent mortality, the dose is contained in parentheses.

Thus, the compounds of the subject invention, confirm the ability to withstand the NMDA-induced lethality in vivo in mice. They compete with 3-(2-carboxypropyl-4-yl)-propyl-1-phosphinic acid (RAF), a known rival of the NMDA-antagonist, for the use of the binding site. Compounds of the invention, therefore, are competing the NMDA-antagonists.

Compounds according to the invention are active against the NMDA induced littelest and are effective in the treatment of disorders of the CNS (Central nervous system) such as seizures, destruction of brain cells and similar neurodegenerative disorders, including senile slabey, epilepsy, oligopore cerebellar atrophy.

Therefore, along with the new compounds, (see above), we offer a way to prevent neurodegenerative disorders induced by overstimulation of the NMDA receptors in the brain and spinal cord exciting amino acids, which contains the application to a mammal suffering from such degerativnye disease, protivokongestevnoe, narasimhadeva amount of a NMDA antagonist, which is the subject of the present invention.

As such, the compounds according to the invention can be applied, pure or with a pharmaceutical carrier to a patient if necessary. The pharmaceutical carrier may be solid or liquid.

Therefore, in accordance with the invention it is also proposed pharmaceutical composition comprising a compound of formula 1, which was given and defined above, or its acceptable from a pharmaceutical standpoint, salt, and acceptable from a pharmaceutical point of view of the media.

A solid carrier can include one or more materials, which may also act as flavouring agents, lubricating agents, agents that increase the solubility, with nazyvausia agents or agents loosening tablets; it may also be forming a capsule material. In powders, the carrier can be a finely powdered solid substance that is mixed with finely ground active ingredient. In tablets, the active ingredient is mixed with carrier having the necessary properties of pressing, in appropriate proportions, and then the mixture gives the desired shape and size. The powders and tablets in the preferred embodiment, contain up to 99% of active ingredient. Appropriate solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugar, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethylcellulose, polyvinylpyrrolidine, waxes with low melting temperature and ion-exchange resin.

Liquid media used in obtaining solutions, suspensions, emulsions, syrups, elixirs and composition under pressure. The active ingredient can be dissolved or suspended in an acceptable from a pharmaceutical point of view, liquid carriers such as water, an organic solvent, a mixture of both, or acceptable from a pharmaceutical point of view of the oils or fats. The liquid carrier can contain other, when the, buffers, preserving agents, flavouring, flavouring agents, suspendresume agents, thickening agents, coloring agents, viscosity regulators, stabilizers or OSMO-regulators. Examples of liquid carriers for tematicheskoe and parenteral administration include water (partially containing additives mentioned above, for example, derivatives of cellulose, in the preferred embodiment, a solution of sodium carboxymethyl cellulose), alcohols (including monohydroxy alcohols and polyhydric alcohols, e.g. glycols) and their derivatives, and oils (e.g. fractionated coconut oil and peanut butter). For parenteral administration the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers used in the compositions of sterile liquid forms for parenteral use. The liquid carrier for the composition contained under pressure, can be halogenosilanes hydrocarbon or other acceptable from a pharmaceutical point of view, the spray material.

Liquid pharmaceutical compositions which are sterile solutions or suspensions can be used, for example, intramuscular, organisations can also be applied tematicheskim way in the form of a composition or in the form of liquid, or solid.

In a preferred embodiment, the pharmaceutical composition is in the form of a unit dose, for example, tablets or capsules. In this form, the composition is divided into unit doses containing appropriate quantities of the active ingredient; in the form of unit doses can be packaged compositions, for example, Packed powders, vials, ampoules, pre-filled syringes or packages containing liquid. The form of a unit dose may be, for example, the capsule or tablet, or it can be the appropriate number of any such compositions in Packed form.

To determine an effective number of connections that you want to apply for relief in degenerative dysfunction of the Central nervous system, the physician needs only to evaluate the effects of NMDA-antagonists in a patient using a gradual increase tematicheskoe dose from about 1 mg/kg to about 20 mg/kg until then, until it reaches the target level symptomatic effects. The mode of subsequent doses can then be modified to achieve Zelenogo result area changes from about 1 to 100 mg/day. Similar techniques can IP the organisations used prophylactically to stop reduction functions of recognition, for example, if the disease of Alzheimer, you can use a more specific approach, for example, by linking the dose of the drug with improved reaction in memory or similar target reactions that may be associated with mitigation overstimulation under the influence of excitatory amino acids.

DERIVATIVES of[2-(AMINO-3,4-DIOXO-1-CYCLOBUTENE-1-YL)AMINO]ALILOVIC}ACIDS of General formula

< / BR>
where R1hydrogen, C1WITH6-alkyl, or phenyl-C1- C7-alkyl;

R2hydrogen, C1WITH6-alkyl, C2- C6alkenyl, or phenyl-C7WITH12-alkyl,

or R1and R2together represent-CH2CH2- CH2C(R6)(R7) CH2- or-CH2C(R8)(R9) - C(R10)(R11)CH2-, where R6, R8and R10independently from each other hydrogen, C1WITH6-alkyl or hydroxyl, R7, R9and R11independently from each other hydrogen or C1WITH6-alkyl;

A1WITH6-alkylen or2WITH6-albaniles;

X group CO2R3where R3hydrogen or C1- C6-alkyl, P(O)(OR4)(OR5), where R4and R5
or their pharmaceutically acceptable salts.

Priority signs:

22.01.91 when R1hydrogen, C1WITH6-alkyl, or phenyl-C7WITH12-alkyl; R2hydrogen, C1- C6-alkyl, C2WITH6alkenyl, or phenyl-C7- C12-alkyl, or R1and R2together represent-CH2CH2CH2C(R6)(R7) CH2- or-CH2C(R8)(R9) - C(R10)(R11)CH2-, where R6R11hydrogen, A and X have the above meanings;

17.12.91 when R1and R2together represent-CH2CH2CH2C(R6)(R7) CH2- or-CH2C(R8)(R9) C(R10)(R11) - CH2-, where R6, R8and R10WITH1- C6is alkyl or hydroxyl; R7, R9and R11WITH1WITH6-alkyl, A and X have the specified values.

 

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The invention relates to medicine and veterinary medicine, in particular to antiviral agents, and can be used to treat AIDS, viral hepatitis and encephalitis
The invention relates to medicine and can be used for the treatment of skin tumors.
The invention relates to the topic of trauma and orthopedics

The invention relates to medicine, in particular to Phthisiology
The invention relates to medicine, in particular for experimental and clinical therapy, and can be used for adaptogenic effects on the body of a person in extreme conditions or undergoing severe disease

The invention relates to new chemical compound, namely glutamate ethyl ester amben

HOOC-CH2-CH2-COHCH2-C6H4-COOC2H5< / BR>
(I) with antiviral activity that involves its use in medical practice

The invention relates to medicine, more specifically concerns a new drug anti-stress, stress-protective and neuroprotective actions

The invention relates to medicine, in particular to pharmacology and gastroenterology
Bronchodilatory // 2024255
The invention relates to medicine, in particular to pulmonology and pharmacology

The invention relates to medicine, namely to addiction

The invention relates to medicine
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